Travelers' Diarrhea (TD) is a common and usually self-limiting diarrheal disease that affects between 20 to 60% of those who travel from developed to low-income countries. International travelers who visit impoverished areas are sentinels for the presence of local enteric pathogens and are particularly susceptible to disease because they are immunologically nave to the pathogens that they encounter in the food and water. The list of prevalent TD pathogens is limited to less than ten bacterial genera (most of them in the family Enterobacteriaceae), several viruses, including norovirus, and a few protozoan parasites. Mixed infections are also prevalent. Paradoxically, as many as 50% of TD cases are pathogen negative, meaning that a causative agent cannot be identified within the stool, yet antibiotic treatment of pathogen negative patients does ameliorate the disease. Our hypothesis is that many cases of pathogen negative TD are due to new microbial agents that have not been discovered because they cannot be cultivated or detected by traditional microbiological methods and assays or that pathogen negative TD may be due to organisms otherwise considered non-pathogenic that have acquired virulent potential. In addition, it is possible that pathogen negative TD is the result of a new form of community disease involving a consortium of gastrointestinal organisms that cause disease. We plan to use a metagenomic whole genome shotgun sequencing approach coupled with bioinformatic comparisons to databases of microbes (bacteria, viruses and small eukaryotes) and statistical correlation analysis in an attempt to identify new organisms, pathogen signatures and microbial consortia uniquely associated with pathogen negative TD. Candidate pathogens will be the subject of preliminary investigations that can later lead to hypothesis-based investigations into their true roles in TD pathogenesis.